Highlights from Recent Cancer Literature
Journal: Cancer Research (2017)

High grade gliomas (HGG) are highly aggressive brain tumors that frequently spread to the subventricular zone (SVZ). To establish the mechanisms by which HGGs spread to the SVZ, Qin and colleagues isolated periventricular metastases at autopsy from DIPG, a type of HGG that originates in the pons and migrates to the SVZ, and injected these isolates into the pons of immunocompromised mice. In all mice, tumors spread to the SVZ. An invasion assay using conditioned media from SVZ promoted migration. Applying 2D electrophoresis and mass spectrometry, and verified by immunodepletion and knockdown, they identified a requirement for the neurite outgrowth-promoting factor pleiotrophin in glioma invasion. The pleiotrophin receptor protein tyrosine phosphatase receptor type ζ was identified as essential for invasion, and knockdown reduced Rho/ROCK activation, a pathway implicated in glioma invasion. Pharmacological and genetic inhibition of a member of the pleiotrophin complex HSP90 using 17-AAG (tanespimycin) and shRNA resulted in reduced invasion to the SVZ. This study provides novel insights into mechanisms of glioma cell invasion and provides a potential therapeutic strategy to limit glioma invasion.Qin EY, Cooper DD, Abbott KL, Lennon J, Nagaraja S, Mackay A, et al. Neural precursor-derived pleiotrophin mediates subventricular zone invasion by glioma. Cell 2017;170:845–59.e19.MYC expression is governed by cis-regulatory elements located upstream and downstream that are activated in cancer. Dave and colleagues define the role of these so-called enhancers during development, using genetically engineered mice with targeted deletion of the upstream Myc-associated super-enhancer region. These mice were viable and showed tissue-specific deficiencies in Myc expression. Intriguingly, in tissues where Myc expression was significantly compromised, downstream gene expression remained unperturbed, suggesting that in the normal physiological context, expression of MYC target genes remains insensitive to reduction in MYC protein abundance. However, these mice showed decreased tumor development, suggesting that super-enhancers are necessary to drive MYC expression at levels required to drive oncogenic transcription. This study sheds light on the differential regulation of MYC-driven transcription in development and disease.Dave K, Sur I, Yan J, Zhang J, Kaasinen E, Zhong E, et al. Mice deficient of Myc super-enhancer region reveal differential control mechanism between normal and pathological growth. Elife 2017;6:e23382. doi: 10.7554/eLife.23382.To determine how closely related a metastasis is to its primary lesion, Yates and colleagues performed whole genome sequencing of matched primary and metastatic breast cancer samples from 17 patients. They also searched for point mutations or copy number variations in 365 known cancer driver genes during breast cancer progression in a large patient cohort. These analyses revealed that clinically relevant mutations present within the primary tumor were also shared by metastatic clones, indicating that cell dissemination occurred late during primary tumor development. Metachronous metastases (locoregional relapses and distant metastases) harbored more somatic mutations and additional driver gene mutations, suggesting that the formation of a metastatic node required further genomic evolution. Nevertheless, the different genetic landscape of relapsed or metastatic breast cancer raises both a challenge to standard-of-care therapies and the potential to harness new therapeutic opportunities to combat breast cancer recurrence.Yates LR, Knappskog S, Wedge D, Farmery JHR, Gonzalez S, Martincorena I, et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell 2017;32:169–84.e7. doi: 10.1016/j.ccell.2017.07.005.While host cells cannot survive at low extracellular pH, low extracellular pH facilitates the migration and invasion of tumor cells. Unlike host cells, tumor cells have transporters and enzymes that help maintain intracellular pH homeostasis. One such transporter, has been of interest for developing small-molecule drugs to prevent metastasis. Payen and colleagues provide evidence to prove the relevance of monocarboxylate transporter MCT1, a passive transporter of lactic acid in metastasis, with roles beyond being a simple transporter of lactic acid. The authors showed that MCT1 activated transcription factor NF-κB, which enhanced tumor cell migration independently of MCT1 transporter activity. Inhibition of MCT1 by pharmacological agents did not affect MCT1-dependent migration, however, silencing or genetic deletion of MCT1 inhibited migration, invasion, and spontaneous metastasis. Thus, MCT1 inhibition using pharmacological agents might not prove effective in preventing tumor metastasis.Payen VL, Hsu MY, Rädecke KS, Wyart E, Vazeille T, Bouzin C, et al. Monocarboxylate transporter MCT1 promotes tumor metastasis independently of its activity as a lactate transporter. Cancer Research; Published OnlineFirst August 21, 2017; doi: 10.1158/0008-5472.CAN-17-0764.Ionizing radiation elicits inflammatory cytokine production, however, the molecular mechanisms mediating this are poorly understood. Harding and colleagues observed onset of type I interferon signaling days following acute damage produced by irradiation. This delay in type I interferon gene expression was coincident with and required mitotic progression of irradiated cells and generation of micronuclei. The DNA-dependent pattern recognition receptor cGAS was localized and enriched at micronuclei, with localization following either nuclear envelope disruption or transient double-strand break production. In a B16 syngeneic mouse model of melanoma, the cGAS-STING pathway was required for tumor regression in response to radiotherapy and anti-CTLA-4 treatment in vivo. These data suggest that loss of micronuclei envelope integrity enables cGAS-STING to access damaged DNA, resulting in paracrine type I interferon signaling and generating a systemic antitumor response. These findings provide an exciting rationale for exploring radioimmunotherapy in future clinical studies.Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 2017;548:466–70.Tumor cells exhibit plasticity and can transition between epithelial and mesenchymal states. The mesenchymal state has been associated with aggressiveness and resistance to various therapies. An in silico analysis of 516 mesenchymal-rich epithelial cell lines to 481 anticancer agents revealed resistance associated with enzymes that promoted long-chain polyunsaturated fatty acids. Increased production of long-chain polyunsaturated fatty acids made mesenchymal cells susceptible to ferroptosis, cell death induced by toxic lipid peroxides, because polyunsaturated fatty acids became substrates for lipid peroxidation. This increased lipid peroxidation metabolism suggested a dependency on lipid peroxidation detoxifying pathways to prevent ferroptosis. Three classes of compounds selectively killed mesenchymal epithelial cancer cells: lipid-modifying agents; compounds that induced ferroptosis oxidation-induced cell death involving lipid hydroperoxides; and statins. This study posits that the intrinsic ability of epithelial cancers to acquire a mesenchymal treatment resistance state converges on increased metabolism of long-chain polyunsaturated fatty acids that can in turn be selectively targeted with agents that prevent lipid peroxidation detoxification.Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017;547:453–7.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.